Gastrointestinal side effects are a common and serious problem with many drugs. These side effects may manifest themselves in nausea or diarrhea or with injury to the gastrointestinal mucosa. Many drugs have been shown to cause damage to the mucosal lining of the esophagus (esophagitis) or the stomach (gastritis). Among the drugs known to cause such damage are non-steroidal anti-inflammatory drugs (“NSAIDs”). See A. A. al-Quorain et. al., “Non Steroidal Anti-inflammatory Drug Induced Gastropathy”, J. Int. Med. Res. 1993, 21(2), 89-97; P. M. Goggins et. al., “Prevalence of Heliobacter Pylori Infection and its Effect on Symptoms and non-Steroidal Anti-inflammatory Drug Induced Gastro-intestinal Damage in Patients with Rheumatoid Arthritis” Gut, 1993, 34(12), 1677-80 ; M. Frezza et. al., “The Histopathology of Non-Steroidal Anti-inflammatory Drug Induced Gastroduodenal Damage: Correlation with Heliobacter Pylori, Ulcers and Haemorrhagic Events” J. Clin. Pathol. 2001, 54(7), 521-5 and references therein. Other drugs known to cause such damage are bisphosphonates. See K. O. Larsen, “Oesophagusskader Relatert till Bisphosphonater” Tidsskr. Nor. Laegeforen 2000, 120(20), 2397-9; D. Y. Graham, H. M. Malaty, “Alendronate and Naproxen Are Synergic for Development of Gastric Ulcers” Arch. Inter. Med. 2001, 161(1), 107-110; F. L. Lanza et. al., “Endoscopic Comparison of Esophageal and Gastroduodenal Effects of Risedronate and Alendronate in Postmenopausal Women” Gastroenterology, 2000, 119(3), 631-8.
In the case of NSAIDs, bisphosphonates and many other drugs, there is much evidence to implicate the solid form of the drug in causing esophagitis and gastritis. See D. Jasperson, “Drug Induced Esophageal Disorders:pathnogenesis, Incidence, Prevention and Management” Drug Saf. 2000, 22(3), 237-249; S. J. Smith et al., “Pill-induced Esophagitis Caused by Oral Rifampin” Ann. Pharmocother. 1999, 33(1), 27-31; J. W. Kikendall, “Pill Esophagitis” J. Clin. Gastroenterol. 1999, 28(4), 298-305; A. Minchoa, D. S. Greenbaum, “Pill Esophagitis Caused by Non-steroidal Antiinflammatoy Drugs” Am. J. Gasterenterol., 1991, 86(8), 1086-9. Such esophagitis is called pill induced esophagitis or pill esophagitis and when causing damage to the stomach lining can be called contact gastritis. These forms of mucosal damage can be mitigated by preventing the physical contact of the drug containing solid dose formulation with the surface of the mucosa.
Pill esophagitis and contact gastritis can be reduced by limiting physical contact between the pill containing the drug and the mucosal lining. Solutions suggested in the literature include coatings to limit esophageal contact, coatings to shorten esophageal transit time and improvements in tablet shape to shorten esophageal transit time. See A. C. Perkins et. al., “The Use of Scintigraphy to Demonstrate the Rapid Esophageal Transit of the Oval Film-coated Placebo Risendronate Tablet Compared to a Round Uncoated Placebo Tablet When Administered with Minimal Volumes of Water” Int. J. Pharm., 2001, 222(2) 295-303; T. S-H. Chen, U.S. patent application Ser. No. 2001/0036475; A. G. Daifotis et. al., U.S. Pat. No. 5,994,329 (enteric coatings and film coatings through which the drug is released). Each of these methods has a drawback. Coatings that come off in the stomach may be removed earlier than planned while in the esophagus leading to esophagitis. Furthermore, such coatings will not prevent gastritis. Coatings or shape improvements that shorten esophageal transit time can help prevent esophagitis but again not gastritis. Enteric coatings can totally envelope the pill until it is in the small intestine. While this can prevent contact esophagitis or gastritis it will not protect against ulceration in the small intestine and will not be desired for a drug whose absorption site is in the upper part of the GI tract (stomach or duodenum).
A further suggestion to prevent contact between the solid particles of the drug formulation and the mucosal lining is to encapsulate the drug totally in a capsule or coating and release the drug slowly through an orifice or through the film coat by diffusion or through micropores. These suggestions can be fulfilled by using an osmotic pump device to deliver the drug or a permeable film coat such as Eudragit NE or Eudragit RL or RS. The osmotic pump idea is not a promising solution to the problem of contact esophagitis and gastritis. While the drug leaves the osmotic pump in solution in most cases, the osmotic agents themselves are ulcerative in high concentrations. The stream of drug plus osmotic agent leaving the orifice causes ulceration, especially if the device has lodged against the mucous membrane See V. Simko et. al., “Increased Risk in Esophageal Obstruction with Slow Release Medications” J. Assoc. Acad. Minor. Phys., 1997, 8(2), 38-42. A permeable film coat can serve as a solution to the problem but it limits the drug release profile attainable since only relatively slower release profiles will be obtained and immediate release, or very short slow release profiles are not compatible with the film coat.
In view of the foregoing, it would be highly desirable to have a versatile solid dosage form that reduces contact between the lining of the gastrointestinal tract and a drug contained in the dosage form, particularly an ulcerative drug. Accordingly, one object of the present invention is to provide a solid dosage form that can release a drug according to a predetermined release profile and reduce contact of the solid drug with the lining of the gastrointestinal tract during transit of the dosage form through the esophagus, stomach and intestine.
A novel set of tooling and tableting process have been invented to produce a dosage form meeting the foregoing stringent requirements on tableting presses that are presently available from commercial sources. Tableting presses are well known and available in many designs, and with an array of features. Some presses with high throughput capacity are designed for large production runs. Others are adapted for application of compression coatings, production of multilayer tablets or engraving. Design features which are desirable in presses to be used with the novel toolset of this invention will become apparent from consideration of the detailed description of the preferred embodiments of the invention which follows.
U.S. Pat. No. 5,071,607 describes a pair of dies (punches) with piercing means biased into a sheathed position, which, when used to compress a coating about an object, pierce the object. The punches are adapted for piercing an osmotic drug dispensing vehicle. The piercing means are integral to the punches. They are moved from a sheathed to an unsheathed position by compressive force from punch actuators. Being integral with the punches, the piercing means are not capable of motion or stasis independent of the motion of the punches.
U.S. Pat. No. 3,146,169 describes a tablet comprising a medicated portion and a non-medicated inert portion of sublimed sulfur, plastic, bone phosphate, barium sulfate, wax, calcium silicate and or aluminum silicate which covers part but not all of the surface of the medicated portion. The function of the inert portion is to expose to the gastric fluids only a portion of the surface of the medicated portion (through a single hole in the inert portion) so as to slow the rate of release relative to a conventional tablet and maintain the rate of release constant. The tablet is made by feeding the space between the upper and lower punch faces of a compression coating machine successive batches of material; first, granules of inert material; second, a preformed core of the medicated material; and third, more granules of the inert material. The upper punch face is provided with a protrusion so that when the punch faces are brought together the inert material is compressed around the inner medicated core in the form of a layer provided with a hole made by the protrusion on the upper punch face. The protrusion is pointed and forms a single hole in the medicated portion as well as the inert portion.
U.S. Pat. No. 5,551,856 describes an apparatus for connecting an assembly of three concentrically aligned movable punches which are independently actuated by hydraulic means to a main body of a pressing machine.
In view of the foregoing, there is a need for a versatile solid dosage form that reduces contact between the mucosa lining the gastrointestinal tract and a solid drug contained in the dosage form and equipment and a process for producing such a dosage form.